WO2008005368A2 - Pipérazines en tant qu'antagonistes de p2x7 - Google Patents

Pipérazines en tant qu'antagonistes de p2x7 Download PDF

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WO2008005368A2
WO2008005368A2 PCT/US2007/015192 US2007015192W WO2008005368A2 WO 2008005368 A2 WO2008005368 A2 WO 2008005368A2 US 2007015192 W US2007015192 W US 2007015192W WO 2008005368 A2 WO2008005368 A2 WO 2008005368A2
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phenyl
optionally substituted
isopropyl
compound
group
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PCT/US2007/015192
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English (en)
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WO2008005368A3 (fr
Inventor
Patrick Betschmann
William A. Carroll
Anna M. Ericsson
Shannon R. Fix-Stenzel
Michael Friedman
Gavin C. Hirst
Nathan S. Josephsohn
Biqin Li
Arturo Perez-Medrano
Michael J. Morytko
Paul Rafferty
Haipeng Chen
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Abbott Laboratories
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Publication of WO2008005368A2 publication Critical patent/WO2008005368A2/fr
Publication of WO2008005368A3 publication Critical patent/WO2008005368A3/fr

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    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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Definitions

  • the P2X 7 purinergic receptor (previously known as P2Z), which is one of a family, of ligand gated ion channels, is present on a variety of cell types known to be involved in inflammatory and immune processes, specifically macrophages, mast cells and (T and .B) lymphocytes.
  • P2Z P2X 7 purinergic receptor
  • Activation of the P2X 7 receptor by extracellular nucelotides, in particular ATP leads to caspase-1 (ICE) activation, a protease required for the processing and release of EL-
  • the P2X 7 R is also known to be a pain sensor in the nervous system is expressed by CNS microglia and peripheral nerves. Experiments using P2X 7 deficient mice demonstrate the role of P2X 7 in the development of pain as these mice were protected from the development of both adjuvant-induced inflammatory pain and partial nerve ligation induced neuropathic pain.
  • the present invention provides a compound of Formula I
  • R 1 is selected from the optionally substituted group consisting of diphenylalkyl, alkoxy, alkoxycarbonylalkyl, alkyl, amino, aryl, arylalkyl, benzyloxy, cycloalkyl, cycloalkylalkyl, heteroaryl and heterocyclyl; or R 1 is A-B wherein A is attached to the nitrogen of the amino and
  • A is -C(O)- or is selected from the optionally substituted group consisting of alkylidenyl, heterocyclyl, ary] and heteroaryl;
  • B is selected from the optionally substituted group consisting of -(CH 2 ),, -C(O)-
  • R 2 is H or -(CH 2 ) n -C(O)O-aIkyl; or R 2 is selected from the optionally substituted group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heterocyclyl; or R 2 is Y-Z wherein Y is attached to X and
  • Y is selected from the group consisting of alkylidenyl, alkenyl, aryl, cycloalkenyl,
  • Z is -NR a (CH 2 ) n -Z 100 , -NR a -(CH 2 ) n -C(O)-Z 100 , -NR a (CHa) n -S(O) 2 -Z 200 , -NR 3 -
  • C(O)-(CH 2 ) D -OH or is selected from the optionally substituted group consisting of ⁇ CH 2 ) n -NR a -C(O)-O(CH 2 ) n -aryl, -alkylNR a R b , aryl, aryloxy, benzyloxy, heteroaryl, heterocyclyl, -C(O)NR a (CH 2 )- OH,- C(O)-O(CH 2 ) n - aryl, -C(O)-R d , -C(O)-NR°R b , -C(O)-NR a -R d , -O-R d and -NR a -R d ; wherein Z 100 is selected from the group consisting of OH, — NR a R b , alkoxy or optionally substituted heterocyclyl; wherein Z 200 is selected from the group consisting of alkyl and optional
  • R 3 , R 4 , R 5 , R fi , R 7 , R 8 , R 9 and R 10 are independently H, COOH, -C(O)-NH 2 , -CH 2 -O- (CHz) 1n -O-CH 2 CH 2 -OCH 3 , -CH 2 -O-CH 2 -O-(CH 2 ) m -OCH 3 or are independently selected from the optionally substituted group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; or R 7 and R 8 taken together with the carbon to which they are attached to form a cycloalkyl attached to the piperazine; or R 9 and R 10 taken together with the carbon atom to which they are attached form a cycloalkyl attached to the piperazine; or R 7 and R 9 taken together with the carbon to which they are attached to form a cycloalkyl group attached to
  • R 8 and R 10 taken together with the carbon atoms to which they are attached form a cycloalkyl group attached to the piperazine; provided that R 3 and R 4 are not cycloalkyl, aryl, heteroaryl or heterocyclyl at the same time; provided that R 5 and R 6 are not cycloalkyl, aryl, heteroaryl or heterocyclyl at the same time; provided that R 7 , R 8 , R 9 and R 10 are not cycloalkyl, aryl, heteroaryl or heterocyclyl at the same time; R" and R b are independently selected from H, alkyl, cycloalkyl and aryl;
  • R c is selected from the optionally substituted group consisting of alkyl, alkoxy, alkoxyalkyl, amino, alkyI-C(O)-NR a R b , cycloalkyl, cycloalkylalkyl, -NR a R b , alkyl-NR a R ⁇ -NH-alkyl-NR a R b , heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phenylalkylamino, -NH-heteroaryl and -NH-heterocyclyl
  • R d is selected from the optionally substituted group consisting of -(CHa) 1n -NH 2 , alkyl, alkoxy, aryl, heteroaryl, heterocyclyl and arylalkyl; m is 1 or 2; and n is 1, 2, 3 or 4; or Q is O; and R 1 is selected from the optionally substituted group consisting of alkyl
  • R 1 is A-B wherein A is selected from the optionally substituted group consisting of methyl, ethyl, phenoxy and phenyl; B is selected from the optionally substituted group consisting of benzyloxy, furanyl, phenoxy and phenyl;
  • X is selected from the group consisting of a bond , C(O) and C(O)NH ;
  • R" is selected from the optionally substituted group consisting of benzimidazolyl, be ⁇ zoxazolyl, benzyl, cyclohexyl, phenyl, piperidinyl, pyrazinyl, pyridazinyl, pyrimidiny], pyrrolo[3,2-dlpyrimidinyl, quinazolinyl quinolinyl, quinoxalinyl and thieno
  • Y is selected from the group consisting of naphthyl, phenyl, pyridazinyl, pyrimidinyl, tetrazolyl and
  • Z is selected fro the optionally substituted group consisting of phenoxy, phenyl and piperazinyl;
  • R 3 is H or isopropyl;
  • R" R 5 , R 7 , R 8 and R 10 are H;
  • R 6 is H, isopropyl or phenyl;
  • R 9 is H. isopropyl or optionally substituted phenyl; provided that X-R 2 is not H; provided that the compound is not
  • R 1 is phenyl substituted with GF 3 , piperidinyl substituted with methyl, cyclohexyl substituted with one or more C(O)OH, methyl, CF 3 , methoxy, F, Cl or H or
  • R 2 is benzyl, phenyl optionally substituted with one or more OH, CI or methoxy, piperidinyl substituted with methyl, pyrimidinyl substituted with Cl or quinolinyl substituted with Cl;
  • R 1 is selected from the group consisting of methyl, ethyl, t-butyl, butyl, cyclohexyl, furanylmethyl, pyridinylmethyl, pyridinylethyl, optionally substituted phenyl, Attorney Docket No 8139.WO.O1
  • substituted phenylpropyl wherein the substituents are selected from the group consisting of Cl, Br, F, methyl, propyl, isobutyl, butyl, t-butyl, OCH3, isopropoxy, O-t-butyl, cyclohexyl, CF 3 , SCH 3 , SO 2 CH 3 and CH 2 C(CF 3 ) 3 ; and
  • R 2 is selected from the group consisting of phenylethyl, 1,2,3-triazolyl, pyridinyl substituted with Cl, quinolinyl substituted with Cl,
  • X is a bond
  • R* is selected the group consisting of from t-butyl, isobutyl, sec-butyl, t-butoxy, isopropyl, CF 3 , ethyl, OCF 3 , halo, n-butyl and n-propyl;
  • R 8 and R 9 are independently H or methyl; R 2 is selected from the group consisting of
  • L is Cl, methyl, CF 3 , OH, NO 2 , CN, Br, I or F; and n is 0, 2 or 3.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof wherein Q is O.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to any of the foregoing inventions wherein X is C(O).
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to any of the foregoing inventions wherein
  • R 1 is selected from optionally substituted group consisting of adamantanyl, benzo[l,3]dioxolyl, benzyl, butyl , t-butyl, C(O)-phenyl, cyclohexyl, cyclopentyl, diphenylmethyl, ethyl, fluorenyl, naphthyl and phenyl; or R 1 is A-B wherein
  • A is selected from the group consisting of ethyl and phenyl; and B is selected from the group consisting of benzyloxy, phenoxy and phenyl; and
  • R 2 is selected from the optionally substituted group consisting of phenyl and benzyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to any of the foregoing inventions wherein
  • R 1 is selected from the optionally substituted group consisting of t-butyl, adamantanyl, benzo[l,3]dioxolyl, benzyl, C(O)-phenyl, cyclohexyl, cyclopentyl, diphenylmethyl, fluorenyl, naphthyl and phenyl; or R 1 is A-B wherein
  • A is selected from the group consisting of ethyl and phenyl; and B is selected from the group consisting of benzyloxy, phenoxy and phenyl; R 6 is phenyl; and
  • R 3 and R 9 are H or isopropyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to any of the foregoing inventions wherein R 1 is selected from the optionally substituted group consisting of benzyl, naphthyl . and phenyl; wherein the benzyl is substituted with methyl or Cl and the phenyl is optionally substituted with one or more methyls; R 2 is benzyl substituted with two OCH 3 ; and R 6 is H.
  • R 1 is selected from the optionally substituted group consisting of benzyl, naphthyl . and phenyl; wherein the benzyl is substituted with methyl or Cl and the phenyl is optionally substituted with one or more methyls; R 2 is benzyl substituted with two OCH 3 ; and R 6 is H.
  • R 1 is selected from the optionally substituted group consisting of benzyl, naphthyl . and phenyl
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to first or second embodiment of the invention wherein X is a bond.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the seventh embodiment of the invention wherein
  • R 1 is selected from the optionally substituted group consisting of methyl, ethyl, propyl, butyl, t-butyl, pentyl, CH 2 CH 2 C(O)-OCH 2 CH 3 , adamantanyl, benzyl, cyclohexyl, indanyl, naphthyl, phenyl, piperidinyl, quinolinyl and thienyl; or R 1 is A-B wherein
  • A is selected from the optionally substituted group consisting of methyl, ethyl phenoxy and phenyl; and B is selected from the optionally substituted group consisting of furanyl, phenoxy and phenyl;
  • R 2 is selected from the optionally substituted group consisting of benzimidazolyl, benzoxazolyl, benzyl, cyclohexyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolo[3,2-d]pyrimidinyl, quinazolinyl and thieno[3,2-d]pyridinyl; or R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of naphthyl, phenyl,
  • Z is selected from the optionally substituted group consisting of phenyl and piperazinyl.
  • R 3 is isopropyl; and R 9 is H, isopropyl or phenyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the seventh and eighth embodiments of the invention wherein
  • R 1 is selected from the optionally substituted group consisting of methyl, propyl, butyl, CH 2 CH 2 C(O)-OCH 2 CH 3 , adamantanyl, benzyl , cyclohexyl, indanyl, naphthyl, phenyl, piperidinyl, quinolinyl and thienyl; or
  • R 1 is A-B wherein
  • A is selected from the optionally substituted group consisting of methyl, ethyl and phenyl;
  • B is selected from the optionally substituted group consisting of furanyl, phenoxy and phenyl; Attorney Docket No 8139.WO.Ol
  • R 2 is selected from the optionally substituted group consisting of benzimidazolyl, benzoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolo[3,2-d]pyrimidinyl, quinazolinyl and thieno[3,2-d]pyrimidinyl; or
  • R 2 is Y-Z wherein Y is selected from the optionally substituted group consisting of pyridazinyl, pyrimidinyl and tetrazolyl;
  • Z is selected from the optionally substituted group consisting of phenyl and piperazinyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the seventh through ninth embodiments of the invention wherein R 1 is selected from the optionally substituted group consisting of naphthyl, phenyl and quinolinyl;
  • R 2 is selected from the optionally substituted group consisting of pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolo[3,2-d]pyrimid ⁇ nyl and thieno[3,2- d]pyrimidinyl; or R 2 is Y-Z wherein Y is pyridazinyl and Z is phenyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the second embodiment of the invention wherein X is C(O)NH wherein the C(O) is attached to the nitrogen of the piperazine.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the second, tenth and eleventh embodiments of the invention wherein
  • R 1 is selected from the optionally substituted group consisting of naphthyl and benzyl;
  • R 2 is 4-chlorophenyl;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 are H; and R 9 is isopropyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the second and tenth through twelfth embodiments of the invention wherein R 1 is benzyl substituted with methyl or Cl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first embodiment of the invention wherein Q is S.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and fourteenth embodiments of the invention wherein X is a bond.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and fifteenth embodiments of the invention wherein R 1 is selected from the optionally substituted group consisting of indazolyl, indolyl, phenyl and quinolinyl; or R 1 is A-B wherein A is phenyl and B is C(O)-NR a R b ;
  • R 2 is selected from the optionally substituted group consisting of benzoxazolyl, benzimidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, ⁇ yr ⁇ olo[2,3- d]pyrimidinyl; or R 2 is Y-Z wherein Y is selected from the optionally substituted group consisting of pyrazinyl, pyridazinyl, pyrimidinyl and quinazolinyl; and Z is r ⁇ (GH 2 ⁇ ,NR a R. b , NH(CH 2 ) n O-alkyl, NH(CH 2 ) n OH or NH(CH 2 ) n S(O) alkyl; or
  • Z is selected from the optionally substituted group consisting of NH(CH 2 ),,- morpholino, NH(CH 2 ) B S(O) 2 (CH 2 ),, -pyrrolidinyl, 4-methoxybenzylamino,
  • R 3 and R 9 are independently selected from H and isopropyl;
  • R 5 and R 6 are independently selected from H and methyl;
  • R 4 , R 7 , R 8 and R 10 are H;
  • R a and R b are independently selected from H and methyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and fourteenth through sixteenth embodiments of the invention wherein R 2 is selected from the optionally substituted group consisting of benzoxazolyl, benzimidazolyl, pyrazinyl , pyridazinyl, pyridinyl, pyrimidinyl and pyrrolo[2,3- d]pyrimidinyl; or
  • R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of pyrazinyl, pyridazinyl and pyrimidinyl;
  • Z is -NH(CH 2 ) n N(CH 3 ) 2 , -NH(CH 2 ) n OCH 3 , -NH(CH 2 ) n OH or -NH(CH 2 ) n - S(O)alkyl; or
  • Z is selected from the optionally substituted group consisting of -NH(CH 2 ) n - morpholino, 4-methoxybenzylamino, C(O)-morpholinyl, -C(O)-OCH 2 - Attorney Docket No 8139.WO.O1
  • phenyl -NH(CH 2 ) n S(O) 2 CH 2 -pyrrolidinyl, 2,3-dihydrobenzofuranyl, benzol l,2,5]oxadiazolyl, benzo[b]thiophenyl, benzylamino, indolyl, isoxazolyl, morpholinyl, phenyl, piperazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, thieno[3,2-d]pyrimidinyl and thienyl; R a and R b are each methyl; and n is 1, 2 or 3.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and fourteenth through seventeenth embodiments of the invention wherein
  • R 2 is selected from the optionally substituted group consisting of benzimidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrrolo[2,3-d]pyrimidinyl; or R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of pyrazinyl, pyridazinyl and pyrimidinyl;
  • Z is -NHCH 2 CH 2 S(O) 2 CH 2 CH 31 -C(O)NHCH 2 CH 2 OH;
  • Z is selected from the optionally substituted group consisting of C(0)-morpholinyl, - C(O)-OCH 2 -phenyl, -NHCH 2 CH 2 -morpholino, benzo[b]thiophenyl, isoxazolyl, morpholinyl, piperazinyl , pyrazolyl, pyridinyl , 4-methoxybenzylamino, phenyl, piperazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, thieno[3,2-d]pyrimidinyl and thienyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and fourteenth through eighteenth embodiments of the invention wherein
  • R 1 is quinolinyl
  • R 2 is Y-Z wherein
  • Y is pyridazinyl
  • Z is benzo[b]thiophenyl substituted with methyl; R 3 is isopropyl; and
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, and fourteenth through nineteenth embodiments of the invention wherein X is C(O)-NH wherein the C(O) is attached to the nitrogen of the piperazine.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof Attorney Docket No 8139.WO.O1
  • R 1 is 2,3-dihydrobenzofuranyl, quinolinyl or phenyl wherein the quinolinyl is optionally substituted with methy] and the phenyl is substituted with -C(O)OCH 3 or -S(O) 2 CH 3 ;
  • R 2 is phenyl substituted with Cl, F or CF 3 ;
  • R 3 is H or isopropyl
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 10 are H
  • R 9 is H or isopropyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first embodiment wherein Q is N-CN.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and twenty-second embodiments wherein X is a bond.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second and twenty-third embodiments wherein R 1 is selected from the optionally substituted group consisting of dihydrobenzofuranyl, indazolyl, isoquinolinyl, isoxazolo[5,4-b]pyridinyl, phenyl, quinolinyl and tetrahydroquinolinyl; or
  • R 1 is A-B wherein
  • A is selected from the optionally substituted group consisting of isoquinolinyl, phenyl and pyrazinyl;
  • R 2 is selected from the optionally substituted group consisting of benzimidazolyl, benzo[4,5]thieno[3,2-d]pyrimidinyl, benzoxazolyl, benzothiazolyl, imidazo[l,2- b]pyridazinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolo[3,2- d]pyrimidinyl, quinazolinyl, quinoxalinyl, thiazolyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl and thienyl; or R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, tetrazolyl, tetrahydroquinolinyl,
  • Z is selected from the optionally substituted group consisting of -C(0)-R d , -C(O)- NR a R b , -C(O)NH(CH 2 ) n OH, -C(O)-O(CH 2 ) n -phenyU- NH(CH 2 ) 0 -morpholino, -NH(CH 2 ) n N(CH 3 ) 2 , -NH(CH 2 ) n N(alkyl) 2 , -NH(CH 2 ) n OCH 3 , -NH(CH 2 ) n , morpholinyl, phenyl, piperazinyl, pyrazolyl and pyridinyl; R 3 and R 7 are H or isopropyl; R 8 is H or phenyl; R 9 is isopropyl or phenyl;
  • R 4 , R 5 , R 6 and R 10 are H;
  • R a and R b are independently selected from H and methyl
  • R c is selected from the optionally substituted group consisting of alkyl and amino; and R d is selected from the optionally substituted group consisting of alkyl, alkoxy, aryl, heteroaryl and heterocyclyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and twenty-second through twenty-fourth embodiments of the invention wherein ⁇
  • R 1 is selected from the optionally substituted group consisting of dihydrobenzofuranyl, indazolyi, isoquinolinyl, isoxazolo[5,4-b]pyridinyl, phenyl, quinolinyl and tetrahydroquinolinyl; or R 1 is A-B wherein A is isoquinolinyl, pyrazinyl or optionally substituted phenyl; and
  • B is C(O)-OCH 2 -phenyI, C(O)-alkyl or C(O)-NR a R b ;
  • R 2 is selected from the optionally substituted group consisting of benzimidazolyl, benzo[4,5]thieno[3,2-d]pyrimidiny], benzoxazolyl, benzothiazolyl, imidazo[l,2- b]pyridazinyl. pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolo[3,2- d]pyrimidinyl, quinazolinyl, quinoxalinyl, thiazolyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl and thienyl; or R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, tetrazolyl and thieno[3,2-
  • Z is selected from the optionally substituted group consisting of -C(O)-R* 3 , -C(O)- NR a R b , -C(O)NHCH 2 CH 2 N(CH 3 ) 2 , -C(O)NHCH 2 CH 2 OH,- C(O)-O-CH 2 - phenyl, -NHCH 2 CH 2 -morpholino, -NHCH 2 CH 2 N(CHj) 2 , - NHCH 2 CH 2 N(CHa) 2 , -NHCH 2 CH 2 CH 2 N(CH 3 ) 2 , -NHCH 2 CH 2 OCH 3 ,.
  • R d is selected from the optionally substituted group consisting of alkoxy, alkyl, isoxazolyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, thiazolyl and triazolyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and twenty-second through twenty-fifth embodiments of the invention wherein
  • R 1 is selected from the optionally substituted group consisting of dihydrobenzofuranyl, indazolyl, isoquinolinyl, phenyl, quinolinyl and tetrahydroquinolinyl; or
  • R 1 is A-B wherein
  • A is unsubstituted isoquinolinyl or phenyl substituted with methyl
  • B is selected from the group consisting of ⁇ C(O)-OCH 2 -phenyl, -C(O)-CH 3 and -
  • R 2 is selected from the optionally substituted group consisting of benzimidazolyl, benzoxazolyl, imidazo[l,2-b]pyridazinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolo[3,2-d]pyrimid ⁇ nyl, quinazolinyl, quinoxalinyl, thiazolyl , thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl and thienyl; or R 2 is Y-Z wherein Y is selected from the optionally substituted group consisting of pyrazinyl,
  • Z is selected from the optionally substituted group consisting of C(O)- morpholinyl, C(O)-piperazinyl, C(O)-piperidinyl, C(O)-pyrrolidinyl, -C(O)- NH-isoxazolyl, -C(O)-NH-phenyl, -C(O)-NH-pyridinyl,- C(O)-NH- thiazolyl,- C(O)NHCH 2 CH 2 OH, NHCH 2 CH 2 -morpholino, phenyl, piperazinyl, pyrazolyl and pyridinyl; and R 9 is isopropyl.
  • R 1 is selected from the optionally substituted group consisting of C(O)-cycloalkyl, benzimidazolyl, benzo[l,3]dioxazolyl, benzothiazolyl, benzyl, cinnolinyl, Attorney Docket No 8139.WO.O1
  • R 1 is A-B wherein
  • A is selected from the optionally substituted group consisting of alkylidenyl, isoquinolinyl, phenyl, pyridinyl and tetrahydroquinolinyl;
  • B is selected from the optionally substituted group consisting of -C(O)-R C , - C(O)CH 2 CH 2 -C(O)-NH 2 , -NH-C(O)-cycloalkyl, -NH-C(O)-(CH 2 ) 2 - cycloalkyl, cycloalkylalkyl, cycloalkyl, heteroaryl, heterocyclyl, heterocycloalky], phenyl and -NH-C(O)-OCH 2 -phenyl;
  • R 2 is selected from the optionally substituted group consisting of benzo[l,3]dioxazolyl, benzo[l,2,5]thiadiazolyl, benzothiazolyl, benzo[b]thienyl 1,1, dioxide, benzyl, -CH 2 C(O)OCH 2 CH 3 , cyclohexyl, dihydrobenzo[l,4]dioxinyl, alkyl, in
  • Z is selected from the optionally substituted group consisting of benzyl, benzyloxy, C(O)-heterocyclyl, phenoxy, phenyl, pyridinyl, thienyl, -CH 2 - NH-C(O)-OCH 2 -phenyl
  • R 3 is H or is selected from the optionally substituted group consisting of alkyl, cycloalkyl, and phenyl
  • R 4 and R 6 are H or methyl
  • R 7 is H or is selected from the optionally substituted group consisting of alkyl, furanyl, pyridinyl, phenyl and thienyl
  • R 8 is H or alkyl;
  • R 9 is H, alkyl or phenyl
  • R 7 and R 8 taken together taken together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl attached to the piperazine;
  • R c is selected from the optionally substituted group consisting of cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second, twenty-seventh and twenty-eight embodiments wherein R 1 is selected from the optionally substituted group consisting of benzimidazolyl, benzo[l,3]dioxazolyl, benzyl, cinnolinyl, cyclopropyl, dihydrobenzofuranyl, y 1 O.O1
  • R 1 is A-B wherein
  • A is attached to the piperazine and A is selected from the optionally substituted group consisting of alkylidenyl, isoquinolinyl, phenyl, pyridinyl and tetrahydroquinolinyl;
  • B is selected from the optionally substituted group consisting Of -C(O)CH 2 CH 2 - cyclopentyl, -C(O)CH 2 -cyclopropyl, -C(O)CH 2 CH 2 -imidazolyl, - C(O)CH 2 CH 2 -piperidinyl, -C(O)CH 2 CH 2 -C(O)-NH 2 , C(O)- tetrahydropyranyl, C(O)-cyclopropyI, -C(O)-CH 2 -pyridinyl, -NH-C(O)- cyclopropyU-NH-C(O)- CH 2 CH 2 -cyclopentyl, cyclohexylmethyl, cyclopropyl, cyclopropylmethyl, morpholinyl, morpholinylmethyl, mo ⁇ holinylethyl, oxazolyl, pentylmethyl, phenyl, piperidinylmethyl
  • Y is selected from the optionally substituted group consisting of methyl, ethyl, phenyl and thienyl; and Z is selected from the optionally substituted group consisting of benzyl, benzyloxy, C(O)-morpholinyl, C(O)-piperazinyl, phenoxy, phenyl, thienyl and- CH 2 -NHC(O)-OCH 2 -phenyl
  • R 3 is H or is selected from the optionally substituted group consisting of methyl, isopropyl, propyl, cyclopropyl, isobutyl and phenyl;
  • R 4 is H or methyl;
  • R 5 is selected from the group consisting of H, isopropyl, methyl and phenyl;
  • R 6 is H, methyl or phenyl ;
  • R 7 is H or is selected from the optionally substituted group consisting of methyl, ethyl, isopropyl, propyl, butyl, isobutyl, propyl, pentyl, C(O)NH 2 , furanyl, pyridinyl, phenyl and thienyl;
  • R 8 is H, methyl, ethyl or propyl;
  • R 9 is H, methyl, isopropyl or phenyl; or Attorney Docket No 8139.WO.O1
  • R 7 and R 8 taken together taken together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl attached to the piperazine.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to first, twenty-second and twenty-eighth through twenty-ninth embodiments of the invention wherein
  • R 1 is selected from the optionally substituted group consisting of indolyl, phenyl, pyridinyl and quinolinyl or R 1 is A-B wherein
  • A is methyl or optionally substituted tetrahydroquinolinyl
  • R 2 is selected from the optionally substituted group consisting of benzo[l,3]dioxazolyl, benzo[l,2,5]thiadiazolyl, benzo[b]thienyl 1,1, dioxide, benzyl, dihydrobenzo[l,4]dioxinyl, indanyl, isopropyl, isoxazolyl, naphthyl, phenyl and thienyl; or R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of methyl, ethyl and phenyl;
  • Z is selected from the optionally substituted group consisting of C(O)- morpholinyl, phenyl, thienyl and -CH 2 -NH-C(O)-OCH 2 -phenyl;
  • R 3 is H or isopropyl;
  • R 5 is H, isopropyl or phenyl;
  • R 6 is H;
  • R 7 is H, methyl, isopropyl, isobutyl, propyl, C(O)NH 2 or phenyl;
  • R 8 is H or methyl; and
  • R 9 is isopropyl;
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the First, twenty-second and twenty-eighth through thirtieth embodiments wherein
  • R 1 is phenyl substituted with methyl or R 1 is unsubstituted quinolinyl; R 2 is unsubstituted dihydrobe ⁇ zo[l,4]dioxinyl, unsubstituted thienyl or phenyl substituted with one or more CN, Cl, F, SO 2 CH 3 or OCH 3 ; or
  • R 2 is Y-Z wherein Y is ethyl and Z is phenyl substituted with one or more C(O)CH 3 or OCH 3 , or Z is unsubstituted CH 2 -NH-C(O)-OCH 2 - ⁇ henyl; Attorney Docket No 8139.WO.O1
  • R 3 is isopropyl; and R 7 is phenyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second and twenty-eighth through thirtieth-first embodiments wherein X is C(O).
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second and twenty-eighth through thirty-second embodiments wherein
  • R 1 is selected from the optionally substituted group consisting of phenyl and quinolinyl
  • R 2 is selected from the optionally substituted group consisting of alkyl, aryl, heteroaryl, heterocyclyl and -NH-CH 2 -C(O)-O-alkyI; or R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of alkylidenyl, heteroaryl and heterocyclyl;
  • Z is selected from the optionally substituted group consisting of [l,2,4]triazolyl, benzotriazolyl, furanyl, imidazolyl, indolyl, isoxazolyl naphthyl, morpholinyl, oxazolyl, phenoxy, phenyl, pyrazolyl, pyridinyl, quinolinyl, thiazolyl thienyl and -NH-CH 2 -C(O)-O-alkyl;
  • R 3 is H or methyl or isopropyl
  • R 5 and R 7 are independently selected from the group consisting of H, methyl, isopropyl and phenyl;
  • R 8 is H or methyl;
  • R 9 is H, isopropyl or phenyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second and twenty-eighth through thirty-third embodiments wherein
  • R 1 is selected from the optionally substituted group consisting of phenyl and quinolinyl
  • R 2 is selected from the optionally substituted group consisting of [l,5]naphthyridinyl,
  • R 2 is Y-X wherein Y is selected from the optionally substituted group consisting of alkylidenyl, isoxazolyl, pyridinyl, pyrazolyl, thiazolyl and thienyl; and Z is selected from the optionally substituted group consisting of [l,2,4]triazolyl, benzotriazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, morpholinyl, naphthyl, oxazolyl, phenoxy, phenyl, pyrazolyl ,
  • R 5 is H, methyl or phenyl
  • R 7 is H, isopropyl or phenyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second, and thirty-second through thirty-fourth embodiments wherein
  • R 2 is selected from the optionally substituted group consisting of adamantanyl, benzyl, indolyl, phenyl, pyrazinyl, pyrazolyl, pyrrolyl, thiazolyl and thienyl; or R 2 is Y-Z wherein Y is selected from the optionally substituted group consisting of methyl, ethyl, propyl, pyridinyl and thienyl; and
  • Z is selected from the optionally substituted group consisting of benzotriazolyl, furanyl, isoxazolyl, morpholinyl, oxazolyl, phenyl, pyrazolyl, pyridinyl and thienyl; R 7 is isopropyl or phenyl; and
  • R 9 is H, isopropyl or phenyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first and twenty-second embodiments wherein X is S(O) 2 .
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second and thirty-sixth embodiments wherein R 1 is optionally substituted phenyl;
  • R 2 is selected from the optionally substituted group consisting of aryl, heteroaryl and heterocyclyl; or
  • R 2 is Y-Z wherein y
  • Y is selected from the optionally substituted group consisting of phenyl, pyrazolyl, pyridinyl and thienyl
  • Z is selected from the optionally substituted group consisting of isoxazolyl, morpholinyl, oxazolyl, phenoxy, phenyl, pyrazolyl, O-pyridinyl, quinolinyl and thiazolyl;
  • R 7 is isopropyl or phenyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second, thirty-sixth and thirty-seventh embodiments wherein R 1 is phenyl substituted with one or more methyl, -NH-C(O)CH 3 or OCH 3 ,
  • R 2 is selected from the optionally substituted group consisting of benzo[l,2,5]oxadioazolyl , benzo[l,2,5]thiadiazolyl, benzo[b]thienyl, benzoxazolyl, benzyl, furanyl, imidazolyl, imidazol[2,l-b]thiazo]yl, indolyl, isoquinolinyl, isoxazolyl, haphthyl, phenyl, pyrazolyl, thiazolyl and thienyl; or R 2 is Y-Z wherein
  • Y is selected from the optionally substituted group consisting of phenyl, pyrazolyl, pyridinyl and thienyl;
  • Z is selected from the optionally substituted group consisting of isoxazolyl, morpholinyl, oxazolyl, phenoxy, pyrazolyl, O-pyridinyl, quinolinyl and thiazolyl.
  • the invention provides pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, enantiomers thereof or prodrugs thereof according to the first, twenty-second and thirty-sixth through thirty-eighth embodiments wherein R 1 is phenyl substituted with methyl or NH-C(O)CH 3 ;
  • R 2 is unsubstituted benzo[l,2,5]oxadioazolyl, unsubstituted benzo[l,2,5]thiadiazolyl, benzoxazolyl substituted with oxo, phenyl substituted with one or more methyl, F, CN, Cl, or OCH 3 or thienyl optionally substituted with methyl; and R 7 is phenyl.
  • a compound of formula (I) or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount thereof is useful in the treatment of a disorder selected from the group comprising depression, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic Attorney Docket No 8139.WO.O1
  • organ transplant rejection including but not limited to bone marrow and solid organ rejection
  • acute or chronic immune disease associated with organ transplantation sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, spora
  • leucopaenia autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjogren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxo
  • such compounds may be useful in the treatment of disorders such as, edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS), proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and
  • angiopathy nootropic or cognition enhancement, amyotrophic lateral sclerosis, ocular angiogenesis, corneal injury, corneal scarring, scleritis, abnormal wound healing, chronic wound healing, burns, diabetes , endotoxic shock, conjunctivitis shock, conjunctivitis, gram negative sepsis, cerebral malaria, cardiac and renal reperfusion injury, thrombosis, organ transplant toxicity, organ transplant rejection, muscle degeneration, allergic dermatitis, hyperresponsiveness of the airway, irritable bowel disease, growth and metastases of malignant cells, myoblastic leukemia, burn injury, ischemic heart disease, varicose veins, an ocular condition, blastoma, teratocarcinoma, Abetalipoprotemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancrea
  • Subacute sclerosing panencephalitis Syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, transplants, trauma/hemorrhage, type HI hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome,
  • Wilson's disease xenograft rejection of any organ or tissue, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, small bowel transplant rejection, spinal ataxia, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chromic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic salicylate intoxication, colorectal carcinoma, conjunctivitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibro
  • dilated congestive cardiomyopathy disorders of the basal ganglia, Down's Syndrome in middle age, drug- induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocyto
  • autoimmune dermatitis autoimmune diabetes, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, utoimmune uveitis, Behcet's disease, blepharitis, bronchiectasis, bullous pemphigoid, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinical isolated syndrome (CIS) with risk for multiple sclerosis, childhood onset psychiatric disorder, dacrocystitis, dermatomyositis, disc herniation, disc prolapse, drug induced immune hemolytic anemia, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Banre syndrome, heart
  • these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stei ⁇ -Leventhal syndrome), and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis. y
  • Compounds of formula (I) of the invention can be used alone or in combination with an additional agent, e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose.
  • the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the compound of the present invention.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e.g., an agent which effects the viscosity of the composition.
  • the combinations which are to be included within this invention are those combinations useful for their intended purpose.
  • the agents set forth below are illustrative for purposes and not intended to be limited.
  • the combinations, which are part of this invention can be the compounds of the present invention and at least one additional agent selected from the lists below.
  • the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
  • the present compounds may be used in conjunction or combination with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine- suppressing antiinflammatory agent, for example with a compound such as acetaminophen, aspirin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and
  • the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; and a sedating or non-sedating antihistamine.
  • a pain reliever such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinep
  • compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neorai®), tacrolimus (FK-506, Prograf®), rapamyci ⁇ (sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCept®); (d) antihistamines (Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphen
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000: 1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • Immunosuppressants within the scope of the present invention further include, but are not limited to, leflunomide, RADOOl, ERL080, FTY720, CTLA-4, antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®) and basiliximab (Simulect®), and antithymocyte globulins such as thymoglobulins.
  • antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®) and basiliximab (Simulect®)
  • antithymocyte globulins such as thymoglobulins.
  • the present methods are directed to the treatment or prevention of multiple sclerosis using a compound of the invention either alone or in combination with a second therapeutic agent selected from betaseron, avonex, azathioprene (Imurek®, Imuran®), capoxone, prednisolone and cyclophosphamide.
  • a second therapeutic agent selected from betaseron, avonex, azathioprene (Imurek®, Imuran®), capoxone, prednisolone and cyclophosphamide.
  • the practitioner can administer a combination of the therapeutic agents, or administration can be sequential.
  • the present methods are directed to the treatment or prevention of rheumatoid arthritis, wherein the compound of the invention is administered either alone or in combination with a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine A, D- penicillamine, infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), auranofin and aurothioglucose.
  • a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine A, D- penicillamine, infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), auranofin and aurothioglucose.
  • the present methods are directed to the treatment or prevention of an organ transplant condition wherein the compound of the invention is used alone or in combination with a second therapeutic agent selected from the group consisting of cyclosporine A, FK-506, rapamycin, mycophenolate, prednisolone, azathioprene, cyclophosphamide and an antilymphocyte globulin. y
  • a compound of formula (I) of the invention may also be combined with agents, such as methotrexate, 6-MP, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodieste
  • IL-l ⁇ converting enzyme inhibitors IL-l ⁇ converting enzyme inhibitors
  • TNFoj converting enzyme (TACE) inhibitors T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g.
  • soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (EnbrelTM and p55TNFRIgG (Lenercept)), sDL-lRI, sIL-lRII, sEL-6R), antiinflammatory cytokines (e.g.
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of formula (I) of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-I receptor antagonists; anti-IL-l ⁇ monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-I, IL-2, 1L-6, DL-7, IL-8, IL-12, IL-15, IL-16, EMAP-I
  • IRAK, NDC, IKK, p38 or MAP kinase inhibitors ); DL-l ⁇ converting enzyme inhibitors; TNF ⁇ converting enzyme inhibitors; T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRII, sIL-6R) and antiinflammatory cytokines (e.g.
  • TNF antagonists for example, anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382; HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)) inhibitors and PDE4 inhibitors.
  • a compound of formula (I) can be combined with corticosteroids, for.
  • budenoside and dexamethasone examples include sulfasalazine, S-aminosalicylic acid; olsaiazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as IL-I, for example, BL-l ⁇ converting enzyme inhibitors and IL-lra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors 6-mercaptopurines; IL-I l; mesalamine: prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole;
  • Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of formula (I) can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; y
  • methotrexate 4-aminopyridine; tizanid ⁇ ne; interferon- ⁇ la (AVONEX; Biogen); interferon- ⁇ lb (BETASERON; Chiron/Berlex); interferon ⁇ -n3) (Interferon Sciences/Fujimoto), interferon- ⁇ (Alfa Wassermann/J&J), interferon ⁇ IA-IF (Serono/I ⁇ hale Therapeutics), Peginterferon ⁇ 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; antibodies to or antagonists of other human cytokines or growth factors and their receptors, for example, TNF, LT, IL-I, IL-2, IL-6, JL-I, IL-8, IL-12 T IL-23, IL-15, IL-16, EMAP-II,
  • a compound of formula (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD 19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD 19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • a compound of formula (I) may also be combined with agents, such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSABDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNF ⁇ x or IL-I (e.g.
  • agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSABDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere
  • IL-I ⁇ converting enzyme inhibitors TACE inhibitors
  • T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6- mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRII, sDL-6R) and antiinflammatory cytokines (e.g. DL-4, IL-IO, IL- 13 and TGF ⁇ ).
  • soluble cytokine receptors e.g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRII, sDL-6R
  • antiinflammatory cytokines e.g. DL-4, IL-IO, IL- 13 and TGF ⁇ .
  • interferon- ⁇ for example, EFN ⁇ la and IFN ⁇ lb
  • Copaxone corticosteroids
  • caspase inhibitors for example inhibitors of caspase-1, IL-I inhibitors, TNF inhibitors, and antibodies to CD40 Hgand and CD80.
  • a compound of formula (I) may also be combined with agents, such as alemtuzumab, dronabinol, Unimed, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, ⁇ -immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THCCBD (cannabinoid agonist) MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-Rl, talampanel, teriflunomide,TGF-beta2, tiplimotide, VLA-4 antagonist
  • Non-limiting examples of therapeutic agents for Angina with which a compound of formula (I) of the invention can be combined include the following: aspirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, amlodipine Attorney Docket No 8139.WO.O1
  • Non-limiting examples of therapeutic agents for Ankylosing Spondylitis with which a compound of formula (I) can be combined include the following: ibuprofen, diclofenac and misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, Sulfasalazine, Methotrexate, azathioprine, minocyclin, prednisone, etanercept, infliximab and adalimumab (Humira®).
  • Non-limiting examples of therapeutic agents for Asthma with which a compound of formula (I) can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone d ⁇ propionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, methylprednisolone, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofena
  • Non-limiting examples of therapeutic agents for COPD with which a compound of formula (I) can be combined include the following: albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproter
  • Non-limiting examples of therapeutic agents for HCV with which a compound of formula (I) can be combined include the following: Interferon-alpha-2a, Interferon-alpha-2b, Interferon-alpha conl, Interferon-alpha-nl, Pegylated interferon-alpha-2a, Pegylated interferon-alpha-2b, ribavirin, Peginterferon alfa-2b + ribavirin, Ursodeoxycholic Acid, Glycyrrhizic Acid, Thymalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention with the following targets: HCV polymerase, HCV protease, HCV helicase and HCV IRES (internal ribosome entry site).
  • Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of formula (I) can be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sod succ, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and Interferon-gamma-
  • Non-limiting examples of therapeutic agents for Myocardial Infarction with which a compound of formula (I) can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril HCl/mag carb, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem hydrochloride, captopril
  • Non-limiting examples of therapeutic agents for Psoriasis with which a compound of formula (I) can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, y
  • desonide pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efali
  • Non-limiting examples of therapeutic agents for Psoriatic Arthritis with which a compound of formula (I) can be combined include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, fcetoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocino
  • Non-limiting examples of therapeutic agents for Restenosis with which a compound of formula (I) can be combined include the following: sirolimus, paclitaxel, everol ⁇ mus, tacrolimus, ABT-57 and acetaminophen.
  • Non-limiting examples of therapeutic agents for Sciatica with which a compound of formula (I) can be combined include the following: hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate/apap, tramadol HCl/acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine
  • NSAIDS for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin
  • COX2 inhibitors for example, Celecoxib, rofecoxib, valdecoxib
  • anti-malarials for example, hydroxychloroquine
  • Steroids for example, prednisone, prednisolone, budenoside, dexamethasone
  • Cytotoxics for example, azathioprine, y
  • a compound of formula (I) may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-I, for example, caspase inhibitors like IL-l ⁇ converting enzyme inhibitors and IL-lra.
  • agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-I, for example, caspase inhibitors like IL-l ⁇ converting enzyme inhibitors and IL-lra.
  • a compound of formula (I) may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies.
  • T cell signaling inhibitors for example, tyrosine kinase inhibitors
  • molecules that target T cell activation molecules for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies.
  • a compound of formula (I) can be combined with IL-Il or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-DL-6 receptor antibody and antibodies to B-cell surface molecules.
  • a compound of formula (I) may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BIyS antibody), TNF antagonists, for example, anti-TNF antibodies, adalimumab (HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)).
  • LJP 394 assay for example, anti-TNF antibodies, adalimumab (HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)).
  • “Pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, acetic acid, trifluoracetic acid, tartaric acid (e.g.
  • (+) or (-)-tartaric acid or mixtures thereof amino acids (e.g. (+) or (-)-amino acids or mixtures thereof), and the like.
  • the compounds of this invention embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations, as appreciated by those of ordinary skill in the art. These salts can be prepared by methods known to those skilled in the art.
  • Certain compounds of formula I which have acidic substituents may exist as salts with pharmaceutically acceptable salts with bases.
  • the present invention includes such salts.
  • Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.
  • Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of formula I may contain one or more chiral centers, and exist in different optically active forms.
  • compounds of formula I may contain one chiral center, the y O
  • e ⁇ antiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of formula I contains more than one chiral center it may exist in diastereoisomeric forms.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of formula I and mixtures thereof.
  • Certain compounds of formula I may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of formula I and mixtures thereof.
  • Certain compounds of formula I may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of compounds of formula I and mixtures thereof.
  • pro-drug refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • An example, without limitation, of a pro-drug would be a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across t ey Docket No 81 9 WO.O1
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -(CHz)C(O)H or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (CrGOalkyl, (C 2 - C] 2 )alkanoyloxymethyl, (C 4 -Ct>)l-(alkanoyloxy)ethyl, l-methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-l- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from
  • exemplary pro-drugs release an alcohol of Formula I wherein the free hydrogen of the hydroxyl substituent (e.g., R 1 contains hydroxyl) is replaced by (C r C 6 )alkanoyloxymethyl, l-((C r C 6 )alkanoyloxy)ethyl, l-methyl-l-((Ci-C 6 )alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylarnino-rnethyl, succinoyl, (Ci- Ce)alkanoyl, arylactyl and ⁇ -aminoacyl, or ⁇ -aminoacyl -o> aminoacyl wherein said ⁇ -aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(O)(OH) 2 , -P(O)(O(Ci -
  • heterocyclic or “heterocyclyl” as used herein, include non-aromatic, ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • heteroatom such as nitrogen, oxygen, or sulfur.
  • heteroaryl as used herein include aromatic and non-aromatic, ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • azaindole benzo(b)thienyl, benzimidazolyl, benzo[l,3]dioxolyl, benzo[l,3]dioxazinyl, benz[l,3,4]oxathiazinyl, dihydrobenz[l,4]oxazinyl, benzo[l,4]oxazinyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzofuranyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[l,2,5]isoxazolyl, benzo[l,2,5]oxadiazolyl, benzo[l,2,5]thiadiazolyl, benzoxadiazolyl, cinnolines, chromenes, dihydrobenzofurans
  • alkenyl groups alkoxy group (which itself can be substituted, such as -O-C,-C 6 -alkyl-OR, -O-d-C 6 -alkyl-N(R) 2 , and OCF 3 ), alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl groups (which itself can also be substituted, such as -Ci-C 6 -alkyl-OR, -Ci-C 6 -alkyl-N(R)2, and -CF 3 ), alkylamino, alkylcarbonyl, alkylester, alkylnitrile, alkylsulfonyl, amino, aminoalkoxy, benzyl, CF 3 , COH, COOH, CN, cycloalkyl, dialkyla
  • alkenyl groups alkyl groups (which itself can also be substituted, such as -CVCe-alkyl-OR, -Ci-C 6 - alkyl-N(R) 2 , and -CF 3 ), -C(O)-O-alkyl, cycloalkyl, phenylcarbonyl (which itself can also be substituted) 1, benzylcarbonyl (which itself can also be substituted), thienylcarbonyl (which itself can also be substituted) and alkylcarbonyl (which itself can also be substituted), benzyl (which itself can also be substituted) and phenyl (which itself can also be substituted).
  • substituted heterocyclic or heterocyclyl
  • substituted heteroaryl substituted heteroaryl
  • heterocyclic group is substituted with one or more substituents that can be made by one of ordinary skill in the art and results in a molecule that is a kinase inhibitor.
  • preferred substituents for the heterocyclyls of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocycloalkoxy, alkyl, alkylcarbonyl, alkylester, alkyl-O-C(O)-, alkyl- heterocyclyl, alkyl-cycloalkyl, alkyl-cycloalkenyl, alkyl-nitrile, alkynyl, amido groups, amino, aminoalkyl, aminocarbonyl, benzyl, carbonitrile, carbonylalkoxy, carboxamido, CF 3 , CN, -C(O)OH, -C(O)H, -C(O)-(O)(CH 3 ) 3 , -OH, -
  • E is a direct bond, O, S, S(O), S(O) 2 , or NR f , wherein R f is H or alkyl and R d and R 6 are independently H, alkyl, alkanoyl or SO 2 -alkyl; or Rd, R 8 and the nitrogen atom to which they are attached together form a five- or six-membered heterocyclic ring.
  • substituted phenyl when used, what is meant is that the phenyl group is substituted with one or more substituents that can be made by one of ordinary skill in the art and results in a molecule that is a kinase inhibitor.
  • preferred substituents for the phenyls of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylester, alkyl -heterocyclyl, alkyl-cycloalkyl, alkyl-cycloalkenyl, alkynyl, amido groups, amino, aminoalkyl, aminocarbonyl, benzyl, carbonitrile, carbonylalkoxy, CF3, CHF 2 , CN, - C(O)OH, -C(O)H, -C(O)-(O)(CH 3 )3, -OH, -C(O)-alkyl, -C(O)-amino, -C(O)-cycloalkyl, -
  • R 0 for each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, -(Ci-Ce)-NRdR-, -E-(CH 2 ),-NR tl R ( ., -E-(CH 2 ),-O- alkyl, -E-(CH 2 ),-S-alkyl, or -E-(CH 2 ),-OH wherein t is an integer from about 1 to about 6;
  • Z 105 for each occurrence is independently a covalent bond, alkyl, alkenyl or alkynyl; and Z 200 for each occurrence is independently selected from an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, alkyl- phenyl, alkenyl-phenyl or alkynyl-phenyl;
  • E is a direct bond, O, S, S(O), S(O) 2 , or NR f , wherein R f is H or alkyl and R d and R 8 . are independently H, alkyl, alkanoyl or SO 2 -alkyl; or R 4 , R 0 and the nitrogen atom to which they are attached together form a five- or six-membered heterocyclic ring.
  • heterocycloalkyl is a heterocyclic group that is linked to a compound by an aliphatic group having from one to about eight carbon atoms.
  • imidazolylethyl, tetrahydropyranylmethyl, morpholinoethyl, morpholinomethyl, piperidinylmethyl and pyrrolidinylmethyl groups are examples of heterocycloalkyl groups.
  • aliphatic or “an aliphatic group” or notations such as “(Co-Cs)” include straight chained or branched hydrocarbons which are completely saturated or which contain one or more units of unsaturation, and, thus, includes alkyl, alkenyl, alkynyl and hydrocarbons comprising a mixture of single, double and triple bonds. When the group is a C 0 it means that the moiety is not present or in other words, it is a bond.
  • alkyl means Cj-Cg and includes straight chained or branched hydrocarbons which are completely saturated.
  • alkyls are methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, t-butyl, tert-butyl, and isomers thereof.
  • alkenyl and alkynyl means C 2 -Cg and includes straight chained or branched hydrocarbons which contain one or more units of unsaturation, one or more double bonds for alkenyl and one or more triple bonds for alkynyl.
  • alkylidenyl means C 1 -C4 bivalent radicals derived from saturated unbranched alkanes by removal of two hydrogen atoms, for example, -CH 2 -, -CH 2 CH 2 -, - CH 2 -CH 2 -CH 2 -, -CH 2 CH 2 -CH 2 CH 2 -.
  • aromatic groups include aromatic carbocyclic ring systems (e.g. phenyl and cyclopentyldienyl) and fused polycyclic aromatic ring systems (e.g. naphthyl and quinolinyl).
  • cycloalkyl means Ca-C 12 monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons which is completely saturated or has one or more unsaturated bonds but does not amount to an aromatic group.
  • Preferred examples of a cycloalkyl group are adamantanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • acyloxy groups are -OC(O)R.
  • alkoxyalkyl includes, but is not limited to, moieties such as -CH 2 -OCH 3 -CH(CHa)-OEt and -CH 2 -OEt-OCH 3 .
  • alkoxyalkoxyalkyl includes, but is not limited to, moieties such as -CH 2 -OEt-OEt and -CH 2 -OEt-OEt-OEt.
  • aryl as used herein includes, but is not limited to, moieties such as fluorene, naphthyl, tetrahydronaphthyl and phenyl.
  • diphenylalkyl includes, but is not limited to, moieties such as methyl disubstituted with phenyl.
  • alkoxy as used herein includes, but is not limited to, moieties such as OCH 3 .
  • arylalkyl includes, but is not limited to, moieties such as benzyl and phenylethyl. y
  • cycloalkylalkyl includes, but is not limited to, moieties such as cyclopropylmethyl, cyclohexylmethyl and cyclopentylmethyl.
  • aminoalkyl as used herein includes, but is not limited to, moieties such as aminopropyl.
  • aminoalkylamine as used herein includes, but is not limited to, moieties such as diethylaminoethylamine.
  • aryloxy as used herein includes, but is not limited to, moieties such as benzyloxy and phenoxy.
  • cycloalkyenyl includes, but is not limited to, moieties such as cyclobutene.
  • aryloxyalkyl includes, but is not limited to, moieties such as benzyloxy.
  • aralkyl as used herein includes, but is not limited to, moieties such as benzyl.
  • One or more compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • a therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein.
  • Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral iise can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arable, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or y
  • Suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or y
  • hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example as an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt
  • An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD cosolvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to ' calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions of the invention may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. Effective Dosage
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art.
  • the therapeutically effective dose can be estimated initially from cellular assays.
  • a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the ICso as determined in cellular assays (i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given protein kinase activity).
  • the IC50 in the presence of 3 to 5% serum albumin since such a determination approximates the binding effects of plasma protein on the compound.
  • serum albumin Such information can be used to more accurately determine useful doses in humans.
  • the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma.
  • a therapeutically effective dose refers to that amount of a compound of Formula I or a combination of two or more such compounds, which inhibits, totally or partially, the progression of a condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can also be an amount which is prophylactically effective.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED 50 (effective dose for 50% maximal response).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 30 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount can also be an amount which is prophylactically effective.
  • the amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al., 1975, in "The y
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of protein kinase using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using the MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • compositions administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • Tablets can be prepared, for example, from the following ingredients. Parts by weight
  • the active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in ethanol.
  • the dry granulate can be blended with the magnesium stearate and the rest of the starch.
  • the mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
  • Tablets can be prepared by the method described in (b) above.
  • the tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1). d) Suppositories
  • active compound in the preparation of suppositories, for example, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein.
  • additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization.
  • the compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate.
  • the additional pharmaceutical agents include, but are not limited to any of the agents, for examples, described in pages 20- 28.
  • the compounds of the invention and the additional pharmaceutical agents act either additively or synergistically.
  • the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone.
  • combinations with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention.
  • the present invention also comprises the use of a compound of formula I as a medicament.
  • a further aspect of the present invention provides the use of a compound of formula I or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenes ⁇ s-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings.
  • the present invention also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of formula I to a mammal, particularly a human being, in need thereof.
  • Agonist-induced Ca 2+ dynamics were assessed in all of the cell lines using the Ca 2+ chelating dye, Fluo-4, in conjunction with a Fluorometric Imaging Plate Reader (FLIPR; Molecular Devices, Sunnyvale, CA) as previously described (Bianchi et al, 1999) with noted minor modifications.
  • FLIPR Fluorometric Imaging Plate Reader
  • the cells were plated out the day before the experiment onto PoIy-D-Ly sine coated black 96 well plates (Becton-Dickinson, Bedford, MA and Sigma, St. Louis MO). Cell concentration was 5 x 10 6 cells per plate.
  • Fluo-4 was dissolved in anhydrous DMSO to a final concentration of 5 ug/ml in DPBS.
  • the dye was loaded onto the adherent cells and the plates were centrifuged for 5 minutes at 1000 rpm. Cells were loaded for at least one hour, but not more than 3 hours and kept in the dark at room temperature. After loading, the unincorporated Fluo-4 was removed by washing with DPBS using a SkanWasher 400 (Molecular Devices, Sunnyvale, CA). All compound solutions were y
  • b Add 40ul DMSO to wells in rows B-H. Make 1:5 serial dilutions of the 2mM compounds (lOul + 40ul DMSO) down to row F. Rows G and H are no drug treatment wells.
  • d Transfer 6ul/well of each dilution into blood plate wells. This is a 1:25 dilution that will give IX compound in 1% DMSO final concentration Add 6ul 25% DMSO to control wells.
  • DMSO Sigma, Cat.# D2650 HEPES: Invitrogen, Cat.# 1530-080 RPMI: Invitrogen, Cat.# 21870-076 LPS: Calbiochem # 437625, 055:B5. ATP: Amersham # 27-1006.
  • TL-Ib Assay Meso Scale Discovery, hBL-lb single-spot assay, Cat # L41 lAGB-1, read on Sector 6000 reader.
  • DMSO Sigma, Cat.# D2650, HEPES: Invitrogen, Cat.# 1530-080 RPMI: Invitrogen, Cat.# 21870-076 LPS: Calbiochem # 437625, 055:B5. ATP: Amersham * 27-1006.
  • mobile phase A was 1OmM ammonium acetate
  • mobile phase B was HPLC grade acetonitrile.
  • a mixture of the amine (1-11 equivalents, preferably 1 equivalent) and diphenylcyanocarboimidate (1 equivalent) is heated in acetonitriJe at about 80 0 C for 4-18 hours (preferably 18 hours) under inert atmosphere.
  • the mixture is allowed to cool to ambient temperature before the reaction volume is approximately doubled with ether.
  • the resulting precipitate is filtered and washed with ether to afford the product.
  • a solution of the isocyanate (1.0-1.5 equivalents, preferably 1.0 equivalent) in an organic solvent (for example tetrahydrofuran, dichloromethane or acetonitrile, preferably tetrahydrofuran) is added dropwise to an organic solution of the amine (1 equivalent) in an organic solvent (for example tetrahydrofuran, dichloromethane or acetonitrile, preferably tetrahydrofuran).
  • the mixture is allowed to stir at ambient temperature for 2-18 hours (preferably 2 hours) before quenching the reaction by addition of water.
  • the product is purified by chromatography or by filtration of the precipitate after dilution with ether (preferably chromatography).
  • Example 1 iV-(4-Chlorophenyl)-4-(iV'-cyano--V-o-tolylcarbamimidoyI)-2- phenylpiperazine-1-carboxamide y
  • a solution of the acid chloride or carboxylic acid that is activated by an equimolar amount of coupling reagent for example EDC, HATU, CDI or 2-chloro-4,6-dimethoxy-l,3,5-triazine with N-methylmorpholine, preferably EDC ⁇ i.0-1.5 equivalents, preferably 1.0 equivalent
  • an organic solvent for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane
  • an organic solvent for example triethylamine, diisopropylethylamine or pyridine, preferably triethylamine; 1.0-3.0 equivalents, preferably 2.0 equivalents
  • an organic solvent for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane.
  • a solution of the sulfonyl chloride (1.0-1.5 equivalents, preferably 1.0 equivalent) in an organic solvent (for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane) is added dropwise to an organic solution of the amine (1 equivalent) and an organic base (for example triethylamine, diisopropylethylamine or pyridine, preferably triethylamine; 1.0-3.0 equivalents, preferably 2.0 equivalents) in an organic solvent (for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane).
  • an organic solvent for example triethylamine, diisopropylethylamine or pyridine, preferably triethylamine; 1.0-3.0 equivalents, preferably 2.0 equivalents
  • the mixture is allowed to stir at ambient temperature for 2-18 hours (preferably 2 hours) before quenching the reaction by the addition of water.
  • the solvent is removed in vacuo before the product was purified by reverse-phase HPLC on a Hyperprep HS C 18 column, 8 ⁇ m, 250 x 21.2 mm; 20% acetonitrile- 50 mM ammonium acetate over 1 min, 20-60% acetonitrile- 50 mM ammonium acetate for 34 min, 60-100% acetonitrile for 1 min, 100% acetonitrile for 5 min, 25 mL/min.
  • l.l'-thiocarbonyldiimidazole (1.0 - 1.2 equivalents, preferably 1.0 equivalent) is added to a solution of the amine (1.0 equivalent) in an organic solvent (for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane).
  • an organic solvent for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane.
  • the mixture is allowed to stir at ambient temperature for 2-18 hours (preferably 2 hours) before the solvent is removed in vacuo.
  • the product is purified by chromatography.
  • l,l'-thiocarbonyldiimidazole (12.94 g, 72.62 mmol) was added to a solution of 5- aminoquinoline (10.47 g, 72.62 mmol) in dichloromethane (40 mL). The mixture is allowed to stir at ambient temperature for 2 hours before the solvent is removed in vacuo.
  • Example 5 3-isopropyl-4-(2-methylquinolin-5-ylthiocarbamoyl)piperazine-l-carboxylic acid(4-chlorophenyl)amide
  • 5-isothiocyanato-2-methylquinoline 611 mg, 3.05 mmol
  • sodium hydrogen cyanamide 195 mg, 3.05 mmol
  • N,N- dimethylformamide 6 mL
  • the reaction was allowed to stir at ambient temperature for 18 hours before the products were purified by reverse-phase HPLC on a Hyperprep HS C18 column, 8 ⁇ m, 250 x 21.2 mm; 20% acetonitrile- 50 mM ammonium acetate over 1 min, 20-60% acetonitrile- 50 mM ammonium acetate for 34 min, 60-100% acetonitrile for 1 min, 100% acetonitrile for 5 min, 25 mL/rnin.
  • the haloheteroarene (1.0-1.5 equivalents, preferably 1.0 equivalent) is added to the amine (1 equivalent) in an organic solvent (for example tetrahydrofuran, dichloromethane, N,N- dimethylformamide, acetonitrile or 1-propanol, preferably 1-propanol).
  • an organic solvent for example tetrahydrofuran, dichloromethane, N,N- dimethylformamide, acetonitrile or 1-propanol, preferably 1-propanol.
  • the mixture is stirred at 25-170 0 C (preferably at 120 0 C).
  • An oil bath or a microwave oven can be used for heating if necessary (preferably microwave oven) for 0.3 -18 hours ( preferably 0.3 or 6 hours).
  • the product is purified by chromatography or by filtration of the precipitate (preferably filtration of the precipitate).
  • m-CPBA 1.0 - 1.3 equivalents, preferably 1.1 equivalents
  • dichloromethane a solution of the quinoline (1.0 equivalent) in dichloromethane.
  • the mixture is allowed to stir at ambient temperature for 6-18 hours (preferably 18 hours) before the reaction is partitioned with saturated sodium bicarbonate solution.
  • the organic layer is separated and dried with sodium sulfate or magnesium sulfate before the solvent is removed in vacuo.
  • the product is purified by reverse-phase HPLC.
  • the product was purified by reverse-phase HPLC on a Hyperprep HS C18 column, 8 ⁇ m, 250 x 21.2 mm; 20% acetonitrile- 50 mM ammonium acetate over 1 min, 20-50% acetonitrile- 50 mM ammonium acetate for 34 min, 50-100% acetonitrile for 1 min, 100% acetonitrile for 5 min, 25 mL/min.
  • cyclopropanecarbaldehyde (0.504 ml, 6.75 mmol) was added to a solution of the l,2,3,4-tetrahydro-5-aminoisoquinoline (1.00 g, 6.75 mmol) in N,N- dimethylformamide (5 mL).
  • sodium triacetoxyborohydride (1.50 g, 7.08 mmol) followed by a catalytic amount of glacial acetic acid (0.02 mL, 0.40 mmol) was added to the reaction.
  • the mixture was allowed to stir at ambient temperature 18 hours before partitioning with a saturated solution of sodium bicarbonate and dichloromethane.
  • a solution of N- (benzyloxycarbonyloxy)succinimide or benzylchloroformate (1.0-2.0 equivalents, preferably 1.0 equivalent) in an organic solvent (for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane) is added dropw ⁇ se to an organic solution of the amine (1 equivalent) and an organic base when benzylchloroformate is used (for example triethylami ⁇ e, diisopropylethylamine or pyridine, preferably triethylamine; 1.0-3.0 equivalents, preferably 2.0 equivalents) in an organic solvent (for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane).
  • an organic solvent for example tetrahydrofuran, dichloromethane or acetonitrile, preferably dichloromethane
  • the mixture is allowed to stir at ambient temperature for 2-18 hours (preferably 8 hours) before the reaction is partitioned with organic solvent (for example dichloromethane or ethyl acetate, preferably dichloromethane) and a saturated solution of sodium bicarbonate.
  • organic solvent for example dichloromethane or ethyl acetate, preferably dichloromethane
  • the organic layer is dried with sodium sulfate or magnesium sulfate before it is filtered.
  • the solvent is removed in vacuo.
  • the product is used in subsequent reactions or is purified by chromatography (preferably chromatography).
  • the W-carbobenzyloxyamine (1 equivalent) and 10% palladium on carbon (0.1 -0.3 equivalents) in an organic solvent for example methanol, ethanol or ethyl acetate, preferably methanol
  • an organic solvent for example methanol, ethanol or ethyl acetate, preferably methanol
  • hydrogen 1 atm - 60 psi, preferably 60 psi
  • the solvent is removed in vacuo.
  • the product is used in subsequent reactions or is purified by chromatography (preferably chromatography).
  • Example 7 4-(Benzo[ ⁇ /]oxazol-2-yl)-iV"-cyano-2-isopropyl-2V-(l,2,3,4- tetrahydroisoquinolin-5-yl)pipcrazine-l-carboximidamide
  • the product was purified by reverse-phase HPLC on a Hyperprep HS C18 column, 8 ⁇ m, 250 x 21.2 mm; 20% acetonitrile- 50 mM ammonium acetate over 1 min, 20-60% acetonitrile- 50 mM ammonium acetate for 34 min, 60-100% acetonitrile for 1 min, 100% acetonitrile for 5 min, 25 mL/min.
  • the Fmoc (1.0-1.5 equivalents, preferably 1.2 equivalents) is added to the amine (1 equivalents) in an organic solvent (for example tetrahydrofuran, dichloromethane, N,N- dimethylformamide, acetonitrile, preferably dichloromethane).
  • an organic solvent for example tetrahydrofuran, dichloromethane, N,N- dimethylformamide, acetonitrile, preferably dichloromethane.
  • the reaction is allowed to stir at 0-25 0 C (preferably 25°C) for 1-I6h (preferably 3 hours).
  • the product is purified by silica gel chromatography.
  • the crude material was purified by silica gel chromatography employing a 60/40 mixture of ethyl acetate heptane as eluent to give 5- amino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid 9H-fluoren-9-ylmethyI ester 5.7g (15.4 mmol).
  • the Fmoc-protected amine is dissolved in 20% piperidine in DMF (3 to 200 mL, preferably 50 mL) and allowed to stir at ambient temperature for 1 to 24 hours (preferably 3 hours). After allotted time the reaction is concentrated and the product is purified by RP-HPLC or silica gel chromatography.
  • Methyl iodide (142 mg, 1 mmol) was added to a solution of JV'-cyano-4-(3,4- dimethoxybenzoyl)-3-phenyl-N-(quinolin-5-yl)piperazine-l-carboximidamide (5 mg, 0.01 mmol) in MeCN (1 mL). After strirring at ambient temperature for 16 h, the product was purified by reverse-phase HPLC on a Hyperprep HS C18 column, 8 ⁇ m, 250 x 21.2 mm;
  • Example 13 Preparation of 4-(2-chloropyr-midin-4-yl)-7V > -cyano-3-phenyl-iV- ⁇ - tolylpiperazine-l-carboximidamide 4-(2-chloropyrimidin-4-yl)-N'-cyano-3-phenyl-/V-o-tolylpiperazine-l-carboximidamide was prepared from ⁇ /'-Cyano-S-phenyl-N-o-tolylpiperazine-l-carboximidamide and 2,4- dichloropyrimidine using general procedure H.
  • Example 14 Preparation of 4-(2-chloropyrimidin-4-yl)-iV > -cyano-2-isopropyl-iV-(l ⁇ ,4- tetrahydroisoquinolin-5-yI)piperazine-l-carboximidamide a) 2-ChIoro-4-(3-isopropylpiperazin-l-yl)pyrimidine
  • 2-Chloro-4-(3-isopropylpiperazin-l-yl)pyrimidine was prepared from 2- isopropylpiperazine and 2,4-dichloropyrimidine using general procedure H. m/z: (M + U) + 24-1.
  • Example 15 Preparation of 4-(iV'-cya ⁇ o-iV-(3-(2-(diinethylamino)acetamido)-2- methyIphenyl)carbamimidoyl)-N-(3-fluorophenyl)-3-isopropylpiperazine-l- carboxamide acetate a) S-Isopropylpiperazin-l-carboxylic acid (3-fluorophenyl)amide
  • Example 16 Preparation of 4-(2-chloropyrimidin-4-yl)--V'-cyano-2-isopropyl-.V-(l,2,3,4- tetrahydroquinolin-5-yl)piperazine-l-carboximidamide
  • 4-(2-chloropyrimidin-4-yl)-N'-cyano-2-isopropyl-N-(l,2,3,4-tetrahydroquinolin-5- yl)piperazine-l-carboximidamide was prepared from 2-chloro-4-(3-isopropylpiperazin-l- yl)pyrimidine and 5-isothiocyanato-l,2,3,4-tetrahydroquinoline according to general procedure G. Retention time: 1.70 min. (method d), m/z: (M + H) + 439.
  • Example 18 Preparation of methyl S-(4-(iV'-cyano--V-o-toIylcarbamimidoyl)-2- phenylpiperazin-l-yl)pyrazine-2-carboxylate acetate methyl 5-(4-(N'-cyano-N-o-tolylcarbamimidoyl)-2-phenylpiperazin-l-yl)pyrazine-2- carboxylate acetate was prepared from 7V-Cyano-3-phenyl-/V-o-tolylpiperazine-l- carboximidamide and 5-chloropyrazine-2-carboxylic acid methyl ester according general procedure H.
  • Example 19 Preparation of -V'-cyano-4-(imidazo[l ⁇ -6]pyr ⁇ dazin-6-yl)-2-isopropyI-iV-(2- methylquinolin-5-yl)piperazine-l-carboximidamide acetate a) 6-(3-Isopropylpiperazin-l-yl)imidazo[l,2-fe]pyridazine 6-(3-Isopropylpiperazin-l-yl)imidazo[l,2-&]pyridazine was prepared from 6- chloroimidazo[l,2-£]pyridazine and 2-isopropylpiperazine according to general procedure H. m/z: (M + H) + 246.
  • N'-cyano-4-(imidazo[l,2-i>]pyridazin-6-yl)-2-isopropyl-N-(2-methylquinolin-5- yl)piperazine-l-carboximidamide acetate was prepared from 6-(3-Isopropylpiperazin-l- yl)imidazo[l,2-fo]pyridazine and 5-isothiocyanato-2-methyIquinolme. Retention time: 1.75 min. (method b), m/z: (M + H) + 454.
  • 6-(3-isopropyl-piperazin-l-yl)-lH-pyrimidin-2-one 6-(3-isopropyl-piperazin-l-yl)-lH-pyrimidin-2-one was prepared from 6-chloro-lH- pyrimidin-2-one and 2-isopropylpiperazine using general procedure ⁇ . m/z: (M + H) + 223.
  • N'-cyano-2-isopropyl-4-(2-oxo-l,2-dihydropyrimidin-4-yl)-N-(quinolin-5-yl)piperazine- 1-carboximidamide and 2-isopropyl-4-(2-oxo-l,2-dihydropyrimidin-4-yl)-N-(quinolin-5- yl)piperazine-l-carbothioamide were prepared from 6-(3-isopropyl-piperazin-l-yl)-li t /- pyrimidin-2-one and quinoline-5-isothiocyanate using general procedure G.
  • Example 22 Preparation of iV-(4-chlorophenyl)-2-phenyl-4-(pyridin-2- ylcarbamothioyl)piperazine-l-carboxamide a) S-Phenylpiperazine-l-carbothioic acid pyridin-3-ylamidc 3-Phenylpiperazine-l-carbothioic acid pyridin-3-ylamide was prepared from 3- isothicyanatopyridine and 2-phenyIpiperazine using general procedure N. m/z: (M + H) + 299.
  • 2-(3-Phenylpiperazin-l-yl)-benzooxazole was prepared from 2-chlorobenzooxazole and 2-phenylpiperazine using general procedure H. m/z: (M + H) + 246.
  • Example 24 4-(1,1-DiOXO-IZf-I-X -6-benzo[rf]isothiazol-3-yl)-2-phenylpiperazine-l- carboxylic acid (4-chlorophenyl)amide a) 2-Phenyl-piperazine-l-carboxylic acid (4-chIoro-phenyl)-amide
  • 2-Phenylpiperazine-l-carboxylic acid (4-chlorophenyl)amide was prepared from 2- phenylpiperazine and 4-chlorophenylisocyanate using general procedure C.
  • (4-chlorophenyl)amide was prepared from 3-chlorobenzo[ ⁇ f
  • Example 25 Preparation of trans- ⁇ r -(4-chlorophenyl)-4-(iV'-cyano-iV-o- tolylcarbamimidoyl) octahydroquinoxaline-l(2H)-carboxamide a) Trans- decahydroquinoxaline and cis-decahydroquinoxaline
  • Trans- /V-(4-chlorophenyl)-4-(N'-cyano-N-o-tolylcarbamimidoyl) octahydroquinoxaline- l(2H)-carboxamide was prepared from trans-4-(JV-cyano-N-o- tolylcarbamimidoyOdecahydroquinoxaline and 4-chlorophenylisocyanate using general procedure C. Retention time: 5.77 min.
  • Cis-4-(A/ t -cyano-N-o-tolylcarbamimidoyl)decahydroquinoxaline was prepared from cis- decahydroquinoxaline and N-cyano- ⁇ '-(2-methylphenyl)carbami ⁇ dic acid phenyl ester using general procedure B. m/z: (M + H) + : 298.
  • Cis- N-(4-chlorophenyl)-4-(AT-cyano-N-o-tolylcarbamiinidoyl) octahydroquinoxaline- l(2//)-carboxamide was prepared from cis-4-(7V-cyano-A ⁇ o- tolylcarbamirnidoyl)decahydroquinoxaline and 4-chlorophenylisocyanate using general procedure C. Retention time: 1.95 min. (method d), m/z: (M + H) + 451
  • N*-cyano-2-isopropyl-4-(pyridazin-3-yl)-iV-(quinolin-5-yl)piperazine-l-carboxiinidamide was prepared from 3-(3-Isopropylpiperazin-l-yl)-pyridazine and quinoline-5- isothiocyanate using general procedure G. Retention time: 1.21 min. (method d), m/z: (M - H) " 399.
  • Example 28 Preparation of N'-cyano-2-isopropyl-4-(pyrimidin-4-yl)-/V-(quinolin-5- yl)piperazine-l-carboximidaniide a) 2-Chloro-4-(3-isopropylpiperazin-l-yl)-pyrimidine 2-Chloro-4-(3-isopropylpiperazin-l-yl)-pyrimidine was prepared from 2- isopropylpiperazine and 2,4-dichloropyrimidine using general procedure H. m/z: (M + H) + 241.
  • Example 30 Preparation of 4-(6-(2-(dimethylamino)ethylamino)pyrimidin-4-yI)-2- isopropy!- ⁇ '-(quinolin-5-yl)piperazine-l-carbothioamide diacetate 4-(6-(2-(Dimethylamino)ethylamino)pyrimidin-4-yl)-2-isopropyl-N-(quinolin-5- yl)piperazine-l-carbothioamide diacetate was prepared from ⁇ -[6-(3-isopropylpiperazin- l-yl)-pyrimidin-4-yl]-yV,N-dimethyl-ethane
  • Example 31 Preparation of iV'-cyano-2-phenyI-4-(6-phenylpyridazin-3-yl)-iV-o- tolylpiperazine-1-carboximidamide a) 3-Phenyl-6-(3-phenylpiperazin-l-yl)-pyridazine
  • 3-Phenyl-6-(3-phenylpiperazin-l-yl)-pyridazine was prepared from 3-chloro-6- phenylpyridazine and 2-phenylpiperazine using general procedure H. m/z: (M + H) + 317.
  • N 1 -cyano-2-phenyl-4-(6-phenylpyridazin-3-yl)-/V-o-tolylpiperazine-l-carboximidamide was prepared from 3-phenyl-6-(3-phenylpiperazin-l-yl)-pyridazine and N-cyano-W-(2- methylphenyl)carbamimidic acid phenyl ester using general procedure B.
  • Example 32 Preparation of 4-(2-chloropyrimidin-4-yl)-JV'-cyano-2-phenyl-/V-o- tolylpiperazine-1-carboximidamide a) 2-ChIoro-4-(3-phenylpiperazin-l-yl)-pyrimidine 2-Chloro-4-(3-phenylpiperazin-l-yl)-pyrimidine was prepared from 2,4- dichloropyrimidine and 2-phenylpiperazine using general procedure H. m/z: (M + H) + 275.
  • 2-(3-Isopropylpiperazin-l-yl)quinazolin-4-ol was prepared from 2-chloro-quinazolin-4-ol and 2-isopropyIpiperazine using general procedure H.
  • N f -cyano-2-isopropyl-4-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-(quinolin-5-yl)piperazine- 1-carboximidamide was prepared from 2-(3-isopropylpiperazin-l-yl)quinazolin-4-ol and quinoline-5-isothiocyanate using general procedure Gtemp. Retention time: 2.12 min. (method d), m/z: (M + H)+ 467.
  • 6-(3-Isopropylpiperazin-l-yl)pyridazin-3-ylamine was prepared from N-(6-chloro- pyridazin-3-yl)-2,2,2-trifluoro-acetamide and 2-isopropylpiperazine using general procedure H. m/z: (M + H) + 222.
  • Example 37 Preparation of 2-isopropyl-4-(6-(pyrrolidine-l-carbonyl)pyridazin-3- yl)-iV-(qui ⁇ olin-5-yl)piperazine-l-carbothioamide a) [6-(3-Isopropylpiperazin-l-yl)pyridazin-3-yl]pyrrolidin-l-ylmethanone A solution of 3-chloro-6-(3-isopropylpiperazin-l-yl)pyridazine (0.123 g, 0.51 mmol), pyrrolidine (0.18 g, 2.55 mmol), triethylamine (0.1 g, 1.02 mmol) and palladium chloride DPPF complex with dichloromethane (1:1) (0.041 g, 0.05 mmol) in DMF (10 mL) was heated at 90 0 C in the atmosphere of carbon monoxide for 4 hours.
  • 2-Isopropyl-4-(6-(pyrrolidine-l-carbonyl)pyridazin-3-yl)-yV-(quinolin-5-yl)piperazine-l- carbothioamide was prepared from [6-(3-Isopropylpiperazin-l-yl)pyridazin-3- yl]pyrrolidin-l-ylmethanone and quinoline-5-isothiocyanate using general procedure N. Retention time: 1.47 min. (method d), m/v. (M - H) " 488.
  • Example 41 Preparation of 4-(3-cyanoquinoxalin-2-yl)- ⁇ r -(3-fluorophenyl)-3- phenylpiperazine-1-carboxamide
  • Example 42 Preparation of iV-(3-fluorophenyl)-3-phenyl-4-(quinoxalin-2- yl)piperazine-l-carboxamide
  • 4-(3-chloroquinoxaHn-2 ⁇ yl) ⁇ N-(3-fluorophenyl)-3-phenylpiperazine-l- carboxamide (0.19 g, 0.39 mmol) in EtOH (45 mL)
  • 10% palladium on carbon 0.05 g was added and the mixture was hydrogenated on the Parr shaker apparatus at 60 psi for 24 hours.
  • N-(3-fluorophenyl)-3-isopropyl-4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazine-l- carboxamide was prepared from 3-phenylpiperazine-l-carboxylic acid (3-fluoro- phenyl)amide and 2-chloro-4-hydroxyquinazoline using general procedure Htemp.
  • Example 44 Preparation of 4-(4-chloroquinazolin-2-yl)-iV-(3-fluorophenyl)-3- isopropylpiperazine-1-carboxamide
  • a suspension of N-(3-fluorophenyl)-3-isopropyl-4-(4-oxo-3,4-dihydroquinazolin-2- yl)piperazine-l-carboxamide ( 0.6 g, 1.47 mmol) in phosphorus oxychloride (4 mL) was heated at 55oC for 4 hours.
  • the reaction mixture was cooled to ambient temperature and added dropwise into a saturated solution of sodium hydrogen carbonate (15 mL).
  • the organic phase was extracted with EtOAc (2x15 mL); the combined organic extracts dried with magnesium sulfate and concentrated.
  • the residue was subjected to preparative RP-
  • Example 46 Preparation of 4-(3,4-dihydroquinazolin-2-yl)- ⁇ r -(3-fluorophenyl)-3- isopropylpiperazine- 1-carboxamide diacetate
  • 4-(4-chloroquinazolin-2-yl)-JV-(3-fluorophenyl)-3-isopropylpiperazine-l- carboxamide (0.12 g, 0.28 mmol)
  • 10% palladium on carbon 0.05 g was added and the mixture was hydrogenated on the Parr shaker apparatus at 60 psi for 24 hours.
  • Example 47 Preparation of ⁇ H3-fluorophenyl)-2-isopropyl-4-(quinazolin-2- yl)piperazine-l -carboxamide iV-(3-fluorophenyl)-2-isopropyl-4-(quinazolin-2-yl)piperazine-l-carboxamide was prepared from 2-(3-Isopropyl-piperazin-l-yl)-quinazoline and 3-fluorophenylisocyanate using general procedure C.
  • Example 49 Preparation of iV-cyano-4-(6-(dimethyIamino)pyrimidin-4-yl)-2- isopropyl- ⁇ ? -(quinolin-5-yl)piperazine-l-carboximidamide a) 4-Chloro-6-(3-isopropylpiperazin-l-yl)pyrimidine 4-Chloro-6-(3-isopropylp ⁇ perazin-l-yl)pyrimidine was prepared from 2- isopropylpiperazine and 4,6-dichloropyrimidine following general procedure H. m/z: (M + H) + 241.
  • [6-(3-Isopropyl-piperazin-l-yl)pyrimidin-4-yl]dimethylamine was prepared from 4- chloro-6-(3-isopropylpiperazin-l-yl)pyrimidine and dimethylamine solution in methanol following general procedure H. m/z: (M + H) + 250.
  • Examples 51 and 52 Preparation of 5-(3-isopropyl-4-(quinolin-5- yIcarbamothioyl)piperazin-l-y.)-N -methylpyrazine-2-carboxamide, 5-(3-isopropyl-4- (quinolin-S-ylcarbamothioyOpiperazin-l-yl)-iV.iV-dimethylpyrazine ⁇ -carboxamide and iV-(2-aminoethyl)-5-(3-isopropyI-4-(quinolin-5-ylcarbamothioyl)piperazin-l-yl)pyrazine- 2-carboxamide a) 3-Isopropyl-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl-5'-carboxylic acid methyl ester S-Isopropyl-SAS.o-tetrahydro ⁇ H-tl ⁇ '
  • Examples 57 and 58 Preparation of 4-(imidazo[l,2-b]pyridazin-6-yl)-2-isopropyl-iV- (quinoHn-5-yl)piperazine-l-carbothioamide acetate and N'-cyano-4-(imidazo[l,2- b]pyridazin-6-yl)-2-isopropyl-iV-(quinolin-5-yl)piperazine-l-carboximidainide
  • the title compound was prepared from Carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-l- yl ester and 3-Isopropyl-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl-5'-carboxylic acid methyl ester following general procedure L.
  • Example 60 Preparation of 5-(4-(iV'-cyano-iV-o-tolylcarbamirnidoyl)-2-phenylpiperazin- l-yl)-iV,-V-diinethylpyrazine-2-carboxainide
  • 3-Isopropyl-3,4,5,6-tetrahydro-2//-[l,2']bipyrazinyl-5'-carboxylic acid methyl ester was prepared from 2-isopropylpiperazine and 5-Chloro-pyrazine-2-carboxylic acid methyl ester following general procedure H. m/z: (M + H) + 265 b) 3-Isopropyl-2 : 3 ⁇ ,6-tetrahydro-[1 ⁇ 2']bipyrazinyI-4 ⁇ '-dicarboxylic acid 4-benzyl ester 5' -methyl ester
  • the title compound was prepared from Carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-l- yl ester and 3-Isopropyl-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl-5'-carboxylic acid methyl ester following general procedure L.
  • the title compound was prepared from 4-(3-Isopropyl-piperazin-l-yl)-2-morpholin-4-yl- thieno[3,2-d]pyrimidine and 5-Isothiocyanatoquinoline following general procedure G.
  • Example 64 Preparation of iV'-cyano-4-(2-(dimethyIamino)thieno[3,2-d]pyrimidin-4-yl)- 2-isopropyl-iV-(quinolin-5-yl)piperazine-l-carboximidamide
  • the title compound was prepared from [4-(3-Isopropyl-piperazin-l-yl)-thieno[2,3- d]pyrimidin-2-yl]-dimethyl-amine and 5-Isothiocyanato-quinoline following general procedure G.
  • Example 65 Preparation of 4-(2-chloropyrimidin-4-yI)-33-dimethyl-7V-(quinolin-5- yl)piperazine-l-carbothioamide acetate Attorney Docket No. 8139.WO.O1
  • the title compound was prepared from SjS-Dimethyl-piperazine-l-carbothioic acid quinolin-5-ylamide and 2,4-dichloropyrimidine following general procedure H.
  • Example 66 Preparation of Tetrahydro-pyran-4-carboxylic acid ⁇ 6-[3-isopropyl-4- (quinolin-5-ylthiocarbamoyl)-piperazin-l-yl]-pyridazin-3-yl ⁇ -amide
  • the title compound was prepared from 4-(6-Amino-pyridazin-3-yl)-2-isopropyl- piperazine-1-carbothioic acid quinoIin-5-ylamide and acetic acid following general procedure D.
  • Example 72 Preparation of benzyl 5-(N'-cyano-2-isopropyl-4-(4-oxo-3,4- dihydroqu ⁇ na2 ⁇ lin-2-y!piperazine-l-carboximidamido)-3,4-dihydroisoquinoline-2(lH)- carboxylate
  • Benzyl 5-(2-isopropyl-4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazine-l- carbothioamido)-3,4-dihydroisoquinoline-2(lH)-carboxylate was prepared from S-Isothiocyanato-S ⁇ -dihydro-lH-isoquinoline ⁇ -carboxylic acid benzyl ester and 2-(3- Isopropylpiperazin-l-yl)-3H-quinazolin-4-one using general procedure G.
  • the solution was cooled to 2° C and sodium borohydride (0.87 g, 22.9 mmol) was added in portions over a ten minute time period.
  • the reaction mixture was allowed to come to ambient temperature and stirred for 3 days.
  • the solvent was removed in vacuo and the residue was partitioned between water (30 mL) and chloroform (20 mL).
  • the aqueous phase was subjected to continuous liquid/liquid extraction with chloroform for 8 hours.
  • the catalyst was filtered off and the solvent was removed under vacuum to yield the title compound (6.09 g, 35.76 mmol) which was used without any further purification.
  • N'-cyano-2-isopropyl-4-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-(l,2,3»4-- tetrahydroisoquinolin-5-yl)piperazine-l-carboximidamide acetate was prepared from benzyl 5-(N'-cyano-2-isopropyl-4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazine-l- carboximidamido)-3,4-dihydroisoquinoline-2(lH)-carboxylate using general procedure M. Retention time: 0.76 min. (method d) m/z: (M + H) + 471.
  • Example 75 Preparation of l-(4-chlorophenylcarbamoyI)-4-(iV'-cyano-7V-o- tolylcarbamimidoyl)piperazine-2-carboxylic acid
  • benzyl chloroformate (0.96 mL, 6.75 mmol) was added dropwise. After stirring at room temperature for 18 hours, the organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography using dichloromethane/ethyl acetate (80/20) to yield the titled product ( 1.34 g, 5.23 mmol).
  • benzyl 2-((cyanoimino)(phenoxy)methylamino)benzylcarbamate was prepared from (2- amino-benzyl)-carbamic acid benzyl ester and diphenyl cyanocarbonimidate using general procedure A. m/z: (M + H) + 401.
  • benzyl 2-(N'-cyano-3-phenytpiperazine-l-carboximidamido)benzylcarbamate benzyl 2-(/V'-cyano-3-phenylpiperazine-l-carboximidamido)benzylcarbamate was prepared from benzyl 2-((cyanoimino)(phenoxy)methylamino)benzylcarbamate and 2- phenylpiperazine using general procedure B. wi/z: (M + H) + 469.
  • benzyl 2-(4-(4-chlorophenylcarbamoyl)-N'-cyano-3-phenylpiperazine-l- carboximidamido)benzylcarbamate was prepared from benzyl 2-( ⁇ T-cyano-3- pheny lpiperazine- 1 -carboximidamido ⁇ enzylcarbamate and 1 -chloro-4-isocyanato- benzene using general procedure C. m/z: (M + H) + 622.
  • 4-benzyl-yV'-cyano-3-(methoxymethyl)-N-o-tolylpiperazine-l-carboximidamide was prepared from the mixture from step c (l-benzyl-2-methoxymethyl-piperazine and 2- methoxymethyl-piperazine) and phenyl ⁇ T-cyano- ⁇ f- ⁇ -tolylcarbamimidate using general procedure B.
  • Example 80 Preparation of ⁇ -(4-chlorophenyl)-4-( ⁇ r '-cyano-iV-o-tolylcarbainimidoyl)- 2-((2-methoxyethoxy)methyl)piperazine-l-carboxamide
  • N-(4-chlorophenyl)-4-( ⁇ /'-cyano-N-o-tolylcarbamimidoyl)-2-((2- methoxyethoxy)methyl)piperazine-l-carboxamide was prepared from ⁇ T-cyano-3-((2- methoxyethoxy)methy V)-N-o-toly lpiperazine- 1 -carboximidamide and 1 -chloro-4- isocyanatobenzene using general procedure C. Retention time: 1.95 min. (method d) m/z: (M + H) + 485.
  • Example 81 Preparation of iV-(4-chlorophenyI)-4-(iV J -cyano-iV-o-tolylcarbaminiidoyl)- 2-(((2-methoxyethoxy)methoxy)methyl)piperazine-l-carboxamide
  • N'-cyano-3-(((2-methoxyethoxy)methoxy)methyl)-N-o-tolylpiperazine-l- carboximidamide was prepared from 2-(2-Methoxy-ethoxymethoxyrnethyl)-piperazine and phenyl W-cyano-N-o-tolylcarbamimidate using general procedure B. m/z: (M + H) + 288.
  • 3-Isopropyl-3,4,5,6-tetrahydro-2//-[l,2']bipyrazinyl-5'-carboxylic acid methyl ester was prepared from 2-isopropylpiperazine and S-chloro-pyrazine ⁇ -carboxylic acid methyl ester using general procedure H.
  • Example 84 Preparation of 5-(4-(iV'-cyano-iV-(2-propyl-l,23,4-tetrahydroisoquinolin-5- yOcarbamimidoyO-S-isopropylpiperazin-l-ylJ- ⁇ /V-diinethylpyrazine- ⁇ -carboxamide
  • Example 86 Preparation of 5-(4-(iV'-cyano-iV-(2-isopropyl-l ⁇ ,3,4- tetrahydroisoquinolin-5-yl)carbamimidoyl)-3-isopropylpiperazin-l-yl)-A ⁇ iV- dimethylpyrazine-2-carboxamide
  • 3-Bromo-6-(3-isopropyl-piperazin-l-yl)-pyridazine was prepared from 2- isopropylpiperazine and 3,6-dibromo-pyridazine using general procedure H. Retention time: 1.17 min. (method d) m/z: (M + H) + 285.
  • 6-(3-Isopropyl-piperazin-l-yl)-pyridazine-3-carboxyIic acid dimethylamide was prepared from 3-bromo-6-(3-isopropyl-piperazin-l-yl)pyridazine using general procedure Q.
  • 6-(4-(/V'-cyano-N-(2-methylquinolin-5-yl)carbamimidoyl)-3-isopropylpiperazin-l-yl)- /V.N-dimethylpyridazine-S-carboxamide was prepared from reaction 6-(3-isopropyl- piperazin-l-yl)-pyridazine-3-carboxyIic acid dimethylamide with 5-isothiocyanato-2- methylquinoline using general procedure G. Retention time: 1.41 min. (method d) m/z: (M + H) + 486.
  • the product was purified by reverse-phase HPLC on a Hyperprep HS C 18 column, 8 ⁇ m, 250 x 21.2 mm; 20% acetonitrile- 50 mM ammonium acetate over 1 min, 20-60% acetonitrile- 50 mM ammonium acetate for 34 min, 60-100% acetonitrile for 1 min, 100% acetonitrile for 5 min, 25 rnL/min.
  • the o-toluidine (0.102 mL, 0.950 mmol ) was added dropwise to a solution of 3,4-dimethoxy-3-cyclobutene-l,2-dione (135 mg, 0.950 mmol) and triethylamine (0.15 mL, 0.950 mmol) in methanol (3 mL).
  • the reaction was allowed to stir at 0 0 C for 2 hours before the dropwise addition of /V-(4-chlorophenyl)-2-phenylpiperazine-l- carboxamide (300 mg, 0.950 mmol) in methanol (3 mL). After the addition was complete, the reaction was allowed to warm to ambient temperature.
  • the product was purified by reverse-phase HPLC on a Hyperprep HS C18 column, 8 ⁇ m, 250 x 21.2 mm;
  • the product was purified by reverse-phase HPLC on a Hyperprep HS C18 column, 8 ⁇ m, 250 x 21.2 mm; 20% acetonitrile- 50 mM ammonium acetate over 1 min, 20-60% acetonitrile- 50 mM ammonium acetate for 34 min, 60-100% acetonitrile for 1 min, 100% acetonitrile for 5 min, 25 mL/min.

Abstract

La présente invention concerne de nouveaux composés de formule (I) ou leurs sels pharmaceutiquement acceptables, leurs métabolites, leurs isomères, leurs énantiomères ou leurs promédicaments de formule (i), dans laquelle les substituants sont tels que définis dans la description, qui sont utiles en tant qu'agents thérapeutiques.
PCT/US2007/015192 2006-06-30 2007-06-29 Pipérazines en tant qu'antagonistes de p2x7 WO2008005368A2 (fr)

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CN114478403B (zh) * 2022-02-28 2024-04-09 中国药科大学 一种含芳香胍基类化合物及其制备方法与应用

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